Epidemiological studies have reported a decrease in the prevalence of Alzheimer's disease in individuals who chronically use non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trials, on the other hand, have been less positive. Nevertheless, it has been proposed that NSAIDs exert part of their effects by reducing long-term cerebral neuroinflammation, although this mechanism has not been proven. In this study, we report that ibuprofen, one of the more widely used non-steroidal anti-inflammatory drugs, was able to alter the ultrastructure of amyloid-β peptide (Aβ) and significantly decrease its association to neuronal membranes, and consequently, its synaptotoxic effect in rat primary hippocampal and cortical cultures at 24 h incubation. In agreement with these results, we found that the decrease in the frequency of calcium transients with Aβ was partly recovered by addition of ibuprofen (8.0 × 10-2 Hz in control; 3.4 × 10-2 Hz in 5 μM Aβ, and 5.9 × 10-2 Hz in the presence of Aβ and 200 μM ibuprofen). Additionally, this effect correlated well with the increment and recovery of miniature spontaneous currents (47 ± 5% of control in 1 μM Aβ alone and 104 ± 14% in the presence of Aβ and ibuprofen). Our results suggest that ibuprofen could be exerting its neuroprotective effect by directly interacting with Aβ and altering its toxic aggregated forms. We postulate that other ibuprofen analogs with better pharmacological properties might have a higher efficacy in AD.